Alkynly-substituted spirocyclic sulfamides for the treatment of alzheimer&#39;s disease

ABSTRACT

Compounds of formula (I) are disclosed. The compounds inhibit gamma-secretase and hence find use in treatment of Alzheimer&#39;s disease

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a U.S. National Phase application under 35 U.S.C. §371 of PCT Application No. PCT/GB03/01771, filed Apr. 24, 2003, whichclaims priority under 35 U.S.C. § 119 from GB Application No. 0209997.6,filed May 1, 2002.

The present invention relates to a novel class of compounds, theirsalts, pharmaceutical compositions comprising them, processes for makingthem and their use in therapy of the human body. In particular, theinvention relates to compounds which modulate the processing of APP byγ-secretase, and hence are useful in the treatment or prevention ofAlzheimer's disease.

Alzheimer's disease (AD) is the most prevalent form of dementia.Although primarily a disease of the elderly, affecting up to 10% of thepopulation over the age of 65, AD also affects significant numbers ofyounger patients with a genetic predisposition. It is aneurodegenerative disorder, clinically characterized by progressive lossof memory and cognitive function, and pathologically characterized bythe deposition of extracellular proteinaceous plaques in the corticaland associative brain regions of sufferers. These plaques mainlycomprise fibrillar aggregates of β-amyloid peptide (Aβ), and althoughthe exact role of the plaques in the onset and progress of AD is notfully understood, it is generally accepted that suppressing orattenuating the secretion of Aβ is a likely means of alleviating orpreventing the condition. (See, for example, ID research alert 19961(2):1–7; ID research alert 1997 2(1):1–8; Current Opinion in CPNSInvestigational Drugs 1999 1(3):327–332; and Chemistry in Britain,January 2000, 28–31.)

Aβ is a peptide comprising 39–43 amino acid residues, formed byproteolysis of the much larger amyloid precursor protein. The amyloidprecursor protein (APP or AβPP) has a receptor-like structure with alarge ectodomain, a membrane spanning region and a short cytoplasmictail. Different isoforms of APP result from the alternative splicing ofthree exons in a single gene and have 695, 751 and 770 amino acidsrespectively.

The Aβ domain encompasses parts of both extra-cellular and transmembranedomains of APP, thus its release implies the existence of two distinctproteolytic events to generate its NH₂- and COOH-termini. At least twosecretory mechanisms exist which release APP from the membrane andgenerate the soluble, COOH-truncated forms of APP (APP_(s)). Proteaseswhich release APP and its fragments from the membrane are termed“secretases”. Most APP_(s) is released by a putative α-secretase whichcleaves within the Aβ domain (between residues Lys¹⁶ and Leu¹⁷) torelease α-APP_(s) and precludes the release of intact Aβ. A minorportion of APP_(s) is released by a β-secretase, which cleaves near theNH₂-terminus of Aβ and produces COOH-terminal fragments (CTFs) whichcontain the whole Aβ domain. Finding these fragments in theextracellular compartment suggests that another proteolytic activity(γ-secretase) exists under normal conditions which can generate theCOOH-terminus of Aβ.

It is believed that γ-secretase itself depends for its activity on thepresence of presenilin-1. In a manner that is not fully understoodpresenilin-1 appears to undergo autocleavage.

There are relatively few reports in the literature of compounds withinhibitory activity towards β- or γ-secretase, as measured in cell-basedassays. These are reviewed in the articles referenced above. Many of therelevant compounds are peptides or peptide derivatives.

WO 01/70677 discloses certain sulphonamido-substituted bridgedbicycloalkyl derivatives which are useful in the treatment ofAlzheimer's disease, but neither discloses nor suggests the compounds ofthe present invention.

The present invention provides a novel class of non-peptidic compoundswhich are useful in the treatment or prevention of AD by modulating theprocessing of APP by the putative γ-secretase, thus arresting theproduction of Aβ and preventing the formation of insoluble plaques.

According to the invention there is provided a compound of formula I:

wherein X represents Ar, L-N(R¹)₂, L-CON(R¹)₂, L-CO₂R¹ or L-CN;

L represents a hydrocarbon chain of 1–7 carbon atoms which, when thechain comprises 2 or more carbon atoms, is optionally interrupted by anoxygen atom;

R¹ represents H or R²; or two R¹ groups attached to a single nitrogenatom may complete a heterocyclic ring of 3–7 members bearing 0–3substituents selected from halogen, oxo, NO₂, CN, CF₃, R², C₂₋₆acyl,C₂₋₆alkenyl, OH, OR², CO₂H, CO₂R², Ar, ArCH₂O, and ArO;

R² represents C₁₋₆alkyl which is optionally substituted with halogen,Ar, NO₂, CN, CF₃, OH or C₁₋₄alkoxy;

R¹⁴ represents H or C₁₋₆alkyl, C₃₋₇cycloalkyl, C₃₋₆cycloalkylC₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, phenyl or benzyl, any of which optionally bearup to 3 halogen substituents or one substituent selected from CN, NO₂,OH, C₁₋₄alkoxy, CO₂H, C₁₋₄alkoxycarbonyl, C₂₋₆acyl, C₂₋₆acyloxy, amino,C₁₋₄alkylamino, di(C₁₋₄alkyl)amino, C₂₋₆acylamino, carbamoyl,C₁₋₄alkylcarbamoyl and di(C₁₋₄alkyl)carbamoyl; and

Ar represents phenyl or heteroaryl either of which optionally bears upto 3 substituents independently selected from halogen, CF₃, NO₂, CN,OCF₃, C₁₋₆alkyl and C₁₋₆alkoxy;

or a pharmaceutically acceptable salt thereof.

Where a variable occurs more than once in formula I or in a substituentthereof, the individual occurrences of that variable are independent ofeach other, unless otherwise specified.

As used herein, the expression “C_(1-x)alkyl” where x is an integergreater than 1 refers to straight-chained and branched alkyl groupswherein the number of constituent carbon atoms is in the range 1 to x.Particular alkyl groups are methyl, ethyl, n-propyl, isopropyl andt-butyl. Derived expressions such as “C₂₋₆alkenyl”, “hydroxyC₁₋₆alkyl”,“heteroarylC₁₋₆alkyl”, “C₂₋₆alkynyl” and “C₁₋₆alkoxy” are to beconstrued in an analogous manner. Most suitably, such groups comprise nomore than 4 carbon atoms.

The expression “C₃₋₇cycloalkyl” as used herein refers to nonaromaticmonocyclic or bicyclic hydrocarbon ring systems comprising from 3 to 7ring atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cyclohexenyl, cycloheptyl and bicyclo[2,2,1]heptyl.

The expression “C₃₋₆ cycloalkyl(C₁₋₆)alkyl” as used herein includescyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl andcyclohexylmethyl.

The expression “C₂₋₆acyl” as used herein refers to (C₁₋₅alkyl)carbonylgroups, such as acetyl, propanoyl and butanoyl, including cycloalkylderivatives such as cyclopentanecarbonyl and cyclobutanecarbonyl andhalogenated derivatives such as trifluoroacetyl.

The expression “heteroaryl” as used herein means a cyclic or polycyclicsystem of up to 10 ring atoms selected from C, N, O and S, wherein atleast one of the constituent rings is aromatic and comprises at leastone ring atom which is other than carbon. Monocyclic systems comprising5 or 6 ring atoms are preferred. Preferably not more than 3 ring atomsare other than carbon. Where a heteroaryl ring comprises two or moreatoms which are not carbon, not more than one of said atoms may be otherthan nitrogen. Examples of heteroaryl groups include pyridinyl,pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, furyl, thienyl,pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl,oxadiazolyl, triazolyl and thiadiazolyl groups and benzo-fused analoguesthereof. Further examples of suitable heteroaryl ring systems include1,2,4-triazine and 1,3,5-triazine.

The term “halogen” as used herein includes fluorine, chlorine, bromineand iodine, of which fluorine and chlorine are preferred.

For use in medicine, the compounds of formula I may advantageously be inthe form of pharmaceutically acceptable salts. Other salts may, however,be useful in the preparation of the compounds of formula I or of theirpharmaceutically acceptable salts. Suitable pharmaceutically acceptablesalts of the compounds of this invention include acid addition saltswhich may, for example, be formed by mixing a solution of the compoundaccording to the invention with a solution of a pharmaceuticallyacceptable acid such as hydrochloric acid, sulphuric acid,methanesulphonic acid, fumaric acid, maleic acid, succinic acid, aceticacid, benzoic acid, oxalic acid, citric acid, tartaric acid, carbonicacid or phosphoric acid. Furthermore, where the compounds of theinvention carry an acidic moiety, suitable pharmaceutically acceptablesalts thereof may include alkali metal salts, e.g. sodium or potassiumsalts; alkaline earth metal salts, e.g. calcium or magnesium salts; andsalts formed with suitable organic ligands, e.g. quaternary ammoniumsalts.

Where the compounds according to the invention have at least oneasymmetric centre, they may accordingly exist as enantiomers. Where thecompounds according to the invention possess two or more asymmetriccentres, they may additionally exist as diastereoisomers. It is to beunderstood that all such isomers and mixtures thereof in any proportionare encompassed within the scope of the present invention.

The compounds of formula I exist as two sets of positional isomers,depending on whether the alkynyl group is attached at an ortho positionrelative to the fused ring junction, or at a meta position relative tosaid junction. Meta attachment is preferred. For each positional isomer,two enantiomeric forms are possible, depending on which of the twoavailable ortho or two available meta positions is occupied. For eachpositional isomer, the invention extends to both enantiomers, as purecompounds or as enantiomeric mixtures in any proportion. Furthermore,structural formulae depicting one enantiomeric form are to be construedas representing both enantiomeric forms, unless otherwise stated.

The compounds of formula I are alkynyl-substituted benzo-fused bridgedbicycloalkane derivatives comprising a spiro-linked cyclic sulphamidemoiety.

In the compounds of formula I, R¹⁴ preferably represents optionallysubstituted C₁₋₆alkyl (such as methyl, ethyl, n-propyl, isopropyl,n-butyl, t-butyl, sec-butyl, cyanomethyl, 2-fluoroethyl, methoxyethyl,trifluoromethyl and 2,2,2-trifluoroethyl), C₃₋₇cycloalkyl (such ascyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl),C₃₋₆cycloalkylC₁₋₆alkyl (such as cyclopropylmethyl, cyclobutylmethyl andcyclopentylmethyl), C₂₋₆alkenyl (such as allyl), C₂₋₆alkynyl (such aspropargyl), or optionally substituted phenyl or benzyl. R¹⁴ very aptlyrepresents n-propyl or 2,2,2-trifluoroethyl, an in a particularembodiment R¹⁴ represents 2,2,2-trifluoroethyl.

In the compounds of formula I, X represents Ar, L-N(R¹)₂, L-CON(R¹)₂,L-CO₂R¹ or L-CN, where Ar, L, R¹ and R² are as defined previously.

In this context, Ar typically represents optionally-substituted phenylor 6-membered heteroaryl, such as pyridyl, pyrimidinyl or pyrazinyl.Suitable substituents include halogen (especially F or Cl),trifluoromethyl and methyl. In a particular embodiment, X represents2-pyridyl, 3-pyridyl or pyrazinyl.

The linking group L represents a hydrocarbon chain comprising from 1 to7 carbon atoms, optionally comprising an oxygen atom in the chain when 2or more carbon atoms are present. Typically, L comprises from 1 to 6,preferably 1 to 5 carbon atoms. Suitable identities for L include —CH₂—,—(CH₂)₄—, —(CH₂)₅—, —(CH₂)₂—O—(CH₂)₂— and —(CH₂)₂—O—CH₂—.

R¹ represents H or R² where R² represents C₁₋₆alkyl which is optionallysubstituted with halogen, Ar, NO₂, CN, CF₃, OH or C₁₋₄alkoxy; or two R¹groups attached to a single nitrogen atom may complete a heterocyclicring of 3–7 members, optionally substituted as defined previously.Examples of groups represented by R¹ include H, methyl, ethyl, propyl,butyl, benzyl, hydroxyethyl and methoxyethyl. When two R¹ groups combineto form a heterocyclic ring, suitable rings include pyrrolidine,piperidine, tetrahydropyridine, piperazine, morpholine, thiomorpholineand 2,5-diazabicyclo[2,2,1]heptane. Preferred ring substituents includehalogen, OH, oxo and R² groups (such as methyl, ethyl, propyl,hydroxymethyl and methoxymethyl), trifluoromethyl, acetyl,trifluoroacetyl, methoxycarbonyl, phenoxymethyl, pyridyl and phenyl,wherein the pyridyl and phenyl groups optionally bear up to 2substituents selected from halogen (especially chlorine or fluorine),C₁₋₆alkyl and C₁₋₆alkoxy. Examples of groups represented by N(R¹)₂include benzylamino, N,N-dimethylamino, piperidin-1-yl, morpholin-4-yl,4-methylpiperazin-1-yl, 4-phenylpiperazin-1-yl,N-(2-methoxyethyl)-N-methylamino, 4-trifluoromethylpiperidin-1-yl,4,4-difluoropiperidin-1-yl, 5-aza-2-oxabicyclo[2.2.1]hept-5-yl,1,2,3,6-tetrahydropyridin-1-yl, N-(pyridin-2-ylmethyl)amino,N,N-bis(2-methoxyethyl)amino, 3,3-difluoropyrrolidin-1-yl,4-hydroxy-4-trifuoromethylpiperidin-1-yl, 3-oxopiperazin-1-yl,3-oxo-4-phenylpiperazin-1-yl, 4-methylpiperidin-1-yl,N-(2,2,2-trifluoroethyl)amino, N-(thiophene-2-ylmethyl)amino,2-phenoxymethylmorpholin-4-yl, 3-(pyridin-3-yl)-pyrrolidin-1-yl,N-(4-phenylmorpholin-2-ylmethyl)amino and 3-hydroxypiperidin-1-yl.Particular groups represented by N(R¹)₂ include benzylamino and4-trifluoromethylpiperidin-1-yl.

A preferred subclass of the compounds of formula I are in accordancewith formula II:

where X is as defined previously.

In one embodiment of this subset, X is selected from 6-memberedheteroaryl, —CH₂N(R¹)₂, —(CH₂)₅N(R¹)₂, —(CH₂)₄CON(R¹)₂, —(CH₂)₄CO₂R²,—(CH₂)₂—O—CH₂CN and —(CH₂)₂—O—(CH₂)₂N(R¹)₂.

Particular compounds in accordance with formula II include those inwhich X represents 2-pyridyl, 3-pyridyl, pyrazinyl,4-trifluoropiperidin-1-ylmethyl, —(CH₂)₅NH—CH₂Ph, —(CH₂)₄CONHCH₂Ph,—(CH₂)₄CO₂H, —(CH₂)₂—O—CH₂CN and —(CH₂)₂—O—(CH₂)₂NH₂.

The compounds of the present invention have an activity as inhibitors ofγ secretase.

The invention also provides pharmaceutical compositions comprising oneor more compounds of this invention and a pharmaceutically acceptablecarrier. Preferably these compositions are in unit dosage forms such astablets, pills, capsules, powders, granules, sterile parenteralsolutions or suspensions, metered aerosol or liquid sprays, drops,ampoules, transdermal patches, auto-injector devices or suppositories;for oral, parenteral, intranasal, sublingual or rectal administration,or for administration by inhalation or insufflation. For preparing solidcompositions such as tablets, the principal active ingredient is mixedwith a pharmaceutical carrier, e.g. conventional tableting ingredientssuch as corn starch, lactose, sucrose, sorbitol, talc, stearic acid,magnesium stearate, dicalcium phosphate or gums or surfactants such assorbitan monooleate, polyethylene glycol, and other pharmaceuticaldiluents, e.g. water, to form a solid preformulation compositioncontaining a homogeneous mixture of a compound of the present invention,or a pharmaceutically acceptable salt thereof. When referring to thesepreformulation compositions as homogeneous, it is meant that the activeingredient is dispersed evenly throughout the composition so that thecomposition may be readily subdivided into equally effective unit dosageforms such as tablets, pills and capsules. This solid preformulationcomposition is then subdivided into unit dosage forms of the typedescribed above containing from 0.1 to about 500 mg of the activeingredient of the present invention. Typical unit dosage forms containfrom 1 to 100 mg, for example 1, 2, 5, 10, 25, 50 or 100 mg, of theactive ingredient. The tablets or pills of the novel composition can becoated or otherwise compounded to provide a dosage form affording theadvantage of prolonged action. For example, the tablet or pill cancomprise an inner dosage and an outer dosage component, the latter beingin the form of an envelope over the former. The two components can beseparated by an enteric layer which serves to resist disintegration inthe stomach and permits the inner component to pass intact into theduodenum or to be delayed in release. A variety of materials can be usedfor such enteric layers or coatings, such materials including a numberof polymeric acids and mixtures of polymeric acids with such materialsas shellac, cetyl alcohol and cellulose acetate.

The present invention also provides a compound of the invention or apharmaceutically acceptable salt thereof for use in a method oftreatment of the human body. Preferably the treatment is for a conditionassociated with the deposition of β-amyloid. Preferably the condition isa neurological disease having associated β-amyloid deposition such asAlzheimer's disease.

The present invention further provides the use of a compound of thepresent invention or a pharmaceutically acceptable salt thereof in themanufacture of a medicament for treating or preventing Alzheimer'sdisease.

Also disclosed is a method of treatment of a subject suffering from orprone to Alzheimer's disease which comprises administering to thatsubject an effective amount of a compound according to the presentinvention or a pharmaceutically acceptable salt thereof.

The liquid forms in which the novel compositions of the presentinvention may be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavoured syrups, aqueous or oilsuspensions, and flavoured emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles. Suitable dispersing or suspendingagents for aqueous suspensions include synthetic and natural gums suchas tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose,methylcellulose, poly(vinylpyrrolidone) or gelatin.

For treating or preventing Alzheimer's Disease, a suitable dosage levelis about 0.01 to 250 mg/kg per day, preferably about 0.01 to 100 mg/kgper day, and especially about 0.01 to 5 mg/kg of body weight per day.The compounds may be administered on a regimen of 1 to 4 times per day.In some cases, however, dosage outside these limits may be used.

The compounds of formula I may be prepared by reaction of triflates IIIwith alkynes HC≡C—X:

where Tf represents trifluoromethanesulphonyl (triflyl) and X and R¹⁴have the same meanings as before. The reaction is typically carried outat elevated temperature (e.g. 90–150° C.) under nitrogen in a sealedcontainer in the presence of (Ph₃P)₄Pd(0), copper iodide, an amine and asolvent such as dioxan. Microwave heating may be employed.

Alternatively, the triflates III may be reacted withtrimethysilylacetylene under similar conditions to provide alkynesIV(a):

where R¹⁴ has the same meaning as before. Hydrolysis of IV(a) (e.g. withLiOH in aqueous THF) provides acetylenes IV(b), which react withcompounds X-G, where G is a suitable leaving group such as halogen(especially Br or I) and X has the same meaning as before, to providecompounds of formula I. The reaction takes place in the presence of(Ph₃P)₄Pd(0), copper iodide and an amine as before, and this route isparticularly suitable when X represents Ar.

Individual compounds in accordance with formula I may be converted todifferent compounds in accordance with formula I by application of knownsynthetic techniques. For example, compounds of formula I in which Xrepresents L-CN may be hydrolysed to the corresponding compounds inwhich X represents L-CO₂H, or reduced to the corresponding compounds inwhich X represents L-CH₂NH₂. Similarly, compounds of formula I in whichX represents L-CO₂H may be coupled with R²OH or (R¹)₂NH to provide thecorresponding esters or amides wherein X represents, respectively,L-CO₂R² or L-CON(R¹)₂. Furthermore, compounds of formula I in which Xrepresents L-CON(R¹)₂ may be reduced to the corresponding amines inwhich X represents L-CH₂N(R¹)₂.

Where they are not commercially available, the above-mentioned reagentsmay be prepared by conventional routes. The synthesis of triflate III inwhich R¹⁴ represents 2,2,2-trifluoroethyl is described in the Examples,and analogous routes may be followed for other identities of R¹⁴.

Where more than one isomer can be obtained from the above-describedreaction schemes, then the resulting mixture of isomers can be separatedby conventional means.

Where the above-described processes for the preparation of the compoundsaccording to the invention gives rise to mixtures of stereoisomers,these isomers may be separated by conventional techniques such aspreparative chromatography. The novel compounds may be prepared inracemic form, or individual enantiomers may be prepared either byenantiospecific synthesis or by resolution. The novel compounds may, forexample, be resolved into their component enantiomers by standardtechniques such as preparative HPLC, or the formation of diastereomericpairs by salt formation with an optically active acid, such as(−)-di-p-toluoyl-d-tartaric acid and/or (+)-di-p-toluoyl-l-tartaricacid, followed by fractional crystallization and regeneration of thefree base. The novel compounds may also be resolved by formation ofdiastereomeric esters or amides, followed by chromatographic separationand removal of the chiral auxiliary.

During any of the above synthetic sequences it may be necessary and/ordesirable to protect sensitive or reactive groups on any of themolecules concerned. This may be achieved by means of conventionalprotecting groups, such as those described in Protective Groups inOrganic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W.Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, JohnWiley & Sons, 1991. The protecting groups may be removed at a convenientsubsequent stage using methods known from the art.

A typical assay which can be used to determine the level of activity ofcompounds of the present invention is as follows:

-   (1) Mouse neuroblastoma neuro 2a cells expressing human app695 are    cultured at 50–70% confluency in the presence of sterile 10 mM    sodium butyrate.-   (2) Cells are placed in 96-well plates at 30,000/well/100 μL in    minimal essential medium (MEM) (phenol red-free)+10% foetal bovine    serum (FBS), 50 mM HEPES buffer (pH7.3), 1% glutamine, 0.2 mg/ml    G418 antibiotic, 10 mM sodium butyrate.-   (3) Make dilutions of the compound plate. Dilute stock solution to    5.5% DMSO/110 μM compound. Mix compounds vigorously and store at    4° C. until use.-   (4) Add 10 μL compound/well. Mix plate briefly, and leave for 18 h    in 37° C. incubator.-   (5) Remove 90 μL of culture supernatant and dilute 1:1 with ice-cold    25 mM HEPES (pH.3), 0.1% BSA, 1.0 mM EDTA (+broad spectrum protease    inhibitor cocktail; pre-aliquotted into a 96-well plate). Mix and    keep on ice or freeze at −80° C.-   (6) Add back 100 μL of warm MEM+10% FBS, 50 mM HEPES (pH7.3), 1%    glutamine, 0.2 mg/ml G418, 10 mM sodium butyrate to each well, and    return plate to 37° C. incubator.-   (7) Prepare reagents necessary to determine amyloid peptide levels,    for example by ELISA assay.-   (8) To determine if compounds are cytotoxic, cell viability    following compound administration is assessed by the use of redox    dye reduction. A typical example is a combination of redox dye MTS    (Promega) and the electron coupling reagent PES. This mixture is    made up according to the manufacturer's instructions and left at    room temperature.-   (9) Quantitate amyloid beta 40 and 42 peptides using an appropriate    volume of diluted culture medium by standard ELISA techniques.-   (10) Add 15 μL/well MTS/PES solution to the cells; mix and leave at    37° C.-   (11) Read plate when the absorbance values are approximately 1.0    (mix briefly before reading to disperse the reduced formazan    product).

Alternative assays are described in Biochemistry, 2000, 39(30),8698–8704.

The Examples of the present invention all had an ED₅₀ of less than 100nM, typically less than 50 nM and in most cases less than 10 nM in atleast one of the above assays.

The following examples illustrate the present invention.

EXAMPLES

Intermediate 1

A mixture of2-hydroxy-5,6,7,8,9,10-hexahydro-6,9-methanobenzo[α][8]annulen-11-one(15 g; J. Org. Chem 1982, 47, 4329), K₂CO₃ (20.5 g) and benzyl bromide(10.6 ml) in DMF (100 ml) was stirred for 48 hrs at room temperature.The reaction was diluted with water (500 ml) and extracted with EtOAc(3×150 ml). The combined organic phases were washed with water (2×300ml), brine (150 ml), dried and concentrated to give a gummy oil whichcrystallized on standing and after trituration with ether the titlebenzyl ether (19.5 g, 90%) as a white solid (360 MHz 1H, δ-CDCl₃) 1.32(2H, m), 1.85 (2H, m), 2.57 (2H, m), 2.87 (4H, m), 5.05 (2H, s), 6.82(2H, m), 7.11 (1H, d, J=8.2), 7.37 (5H, m).

A solution of the product from Step 1 (20 g, 68 mmol), (+/−)tert-butylsulfinamide (9.2 g, 76 mmol) and titanium (IV) ethoxide (tech., 29.2 mL,140 mmol) in dry THF (140 mL) was stirred and heated at reflux undernitrogen for 4 hours. The reaction was allowed to cool to roomtemperature and poured into rapidly stirred brine (160 mL). The mixturewas stirred for 20 minutes, then filtered through Hyflo®, washing withethyl acetate. The filtrate was transferred to a separating funnel. Thelayers were separated, and the aqueous layer was extracted with ethylacetate (×1). The combined organic extracts were washed with brine, thendried (Na₂SO₄), filtered and evaporated. The residue was purified bychromatography on silica, eluting with 20→30% ethyl acetate/hexanes, togive the imine (24.9 g, 93%) as a colourless solid. MS(ES+) 396, MH⁺.

Sodium hydride (60% dispersion in oil, 3.8 g, 95 mmol) was addedportionwise to a stirred suspension of trimethyl sulfoxonium iodide (21g, 95 mmol) in dry DMSO (150 mL) at room temperature under nitrogen.After 90 minutes at room temperature, a solution of the product fromStep 2 (24.9 g, 95 mmol) in dry DMSO (250 mL) was added such that theinternal temperature remained below 30° C. The mixture was stirred atroom temperature for 4 hours, then quenched with water (1 L). Theprecipitate was collected by filtration. The solid was taken up indichloromethane and washed with brine. The organic layer was dried(Na₂SO₄), filtered and evaporated. The residue was purified bychromatography on silica, eluting with 5→10% ethylacetate/dichloromethane, to give the aziridine (23.2 g, 90%) as acolourless solid. MS(ES+) 410, MH⁺.

Trifluoroethyl amine (70 mL, 880 mmol) was added to a stirred suspensionof the product from Step 3 (68.4 g, 167 mmol) and anhydrous zinc iodide(54 g, 170 mmol) in dry 1,2-dichloroethane (300 mL) at room temperatureunder nitrogen. The resulting solution was heated at 75° C., protectedfrom light for 24 hours, an additional portion of trifluoroethyl amine(70 mL, 880 mmol) added and the reaction maintained at 75° C. for afurther 16 hours. The reaction was allowed to cool, then diluted withdichloromethane (500 mL) and water (400 mL). Sufficient sodium carbonatewas then added to adjust the aqueous layer to ˜pH 11. The small amountof precipitate was removed by filtration through Hyflo® The layers wereseparated and the aqueous layer was extracted with dichloromethane (×3).The combined organic extracts were dried (Na₂SO₄), filtered andevaporated. The residue was purified by chromatography on silica,eluting with 5→10% ethyl acetate/dichloromethane, then with 10→20%methanol/dichloromethane, to give the diamine (59.6 g, 88%) as a thickoil. MS(ES+) 405, MH⁺.

A solution of the product from Step 4 (59.6 g, 147 mmol) and sulfamide(42.5 g, 442 mmol) in dry pyridine (350 mL) was stirred and heated atreflux under nitrogen for 4 hours. The reaction was allowed to cool,then the pyridine was removed in vacuo. The residue was azeotroped withtoluene (×2) and the residue partitioned between dichloromethane (400mL) and 1N hydrochloric acid (400 mL). The layers were separated and theaqueous layer was extracted with dichloromethane (3). The combinedorganic extracts were dried (Na₂SO₄), filtered and evaporated. Theresidue was purified by chromatography on silica, eluting withdichloromethane, then 1→2→4% ethyl acetate/dichloromethane to give thecyclic sulfamide (53 g, 80%) as a colourless solid. ¹H NMR (360 MHz,CDCl₃) δ_(H) 1.34 (2H, m), 1.70 (2H, m), 2.41 (2H, m), 2.62 (2H, m),3.11 (2H d, J=15.9), 3.20 (1H, d, J=15.9), 3.42 (2H, ABq, J=9.3, 13.3),3.67 (2H, dq, J=2.2, 8.7), 4.76 (1H, s), 5.02 (2H, s), 6.72 (2H, m),6.99 (1H, d, J=7.8), 737 (5H, m).

A solution of the product from Step 5 (3.9 g, 8.4 mmol) inmethanol/ethyl acetate (4:1, 150 mL) was hydrogenated at 35 psi over 10%palladium on carbon (500 mg) for 4 hours at room temperature. Thecatalyst was removed by filtration through Hyflo®. The filtrate wasevaporated, and the residue was purified by filtration through a pad ofsilica, eluting with 50% ethyl acetate/dichloromethane to give thephenol (3.2 g) colourless solid. ¹H NMR (360 MHz, d₆-DMSO) δ_(H) 1.06(2H, m), 1.65 (2H, m), 2.29 (2H, m), 2.42 (2H, m), 3.04 (1H, d, J=15.6),3.11 (1H, d, J=15.6), 3.43 (2H, s), 3.99 (2H, brq, J=9.6), 6.47 (2H, m),6.85 (1H, d, J=8), 7.93 (1H, s), 9.02 (1H, s).

Pyridine (2.1 mL, 26 mmol) was added dropwise to a stirredsolution/suspension of the product from Step 6 (7.7 g, 20 mmol) andtriflic anhydride (4.3 mL, 25.6 mmol) in dry dichloromethane (200 mL) at0° C. under nitrogen. The cooling bath was removed and the reaction wasstirred at room temperature for 4 hours. Water (300 mL) was added andthe layers were separated. The aqueous layer was extracted withdichloromethane (×2). The combined extracts were washed with brine (×1),then dried (Na₂SO₄), filtered and evaporated. The residue was purifiedby chromatography on silica, eluting with 5% ethylacetate/dichloromethane, to give the triflate (6.7 g, 65%) as an offwhite solid. ¹H NMR (360 MHz, d₆-DMSO) δ_(H) 0.99 (2H, m), 1.71 (2H, m),2.38 (2H, brm), 2.69 (2H, m), 3.16 (1H, d, J=15.7), 3.18 (1H, d,J=15.7), 3.46 (2H, s), 4.02 (2H, brq, J=9.6), 7.18–7.31 (3H, m), 8.04(1H, s).

Example 1

Step 1

4-Trifluoromethylpiperidine (2.0 g, 13 mmol) was added to a solution ofpropargyl bromide (80 wt. % 5.4 g, 36 mmol) in ethanol (30 ml).Potassium carbonate (5.4 g, 39 mmol) was added and the mixture wasstirred at room temperature for 20 hours. The mixture was filtered andthe solids washed with ethyl acetate. The filtrate was evaporated invacuo, diluted with sodium hydrogen carbonate (sat, 50 ml) and extractedwith ethyl acetate (2×40 ml). The extracts were washed with brine, dried(MgSO₄) and evaporated in vacuo to provide1-propargyl-4-trifluoromethylpiperidine as a brown oil (795 mg, 32%).(ES+) 192 ([MH]⁺).

Step 2

A mixture of Intermediate 1 (200 mg, 0.39 mmol), the product from Step 1(148 mg, 0.78 mmol), tetrakis-triphenylphospine palladium(0) (23 mg, 5mol %), triphenyl phosphine (10 mg, 10 mol %) and copper iodide (7.6 mg,10 mol %) in piperidine (2 ml), in a crimp-top microwave vial, wassealed, purged with nitrogen and then irradiated in the SmithSynthesizer Microwave to 150° C. for 15 minutes. The reaction wasdiluted with sodium hydrogen carbonate (sat, 25 ml) and extracted withethyl acetate (2×25 ml). The extracts were washed with water (10 ml) andbrine, dried (MgSO₄) and evaporated in vacuo to a brown gum, which waspurified by flash column chromatography on silica eluting with 20 to 30%EtOAc in isohexane to give a beige gum. The gum was further purified bypreparative TLC on silica eluting with 20% EtOAc in isohexane to givethe title compound as a white solid (42 mg, 20%). δ (¹H, 400 MHz, CDCl₃)1.24–1.35 (2H, m), 1.64–1.75 (4H, m), 1.88–1.92 (2H, m), 1.99–2.08 (1H,m), 2.25 (2H, dd, J=11.7 & 2.1 Hz), 2.42–2.46 (2H, m), 2.57–2.72 (2H,m), 3.03–3.06 (2H, m), 3.18 (2H, dd, J=16.0 & 7.4 Hz), 3.43 (2 h, s),3.52 (2H, s), 3.64–3.70 (2H, m), 4.68 (1H, brs), 7.03 (1H, d, J=7.8 Hz)and 7.18–7.20 (2H, m). (ES+) 550 ([MH]⁺).

Example 2

Step 1

A solution of Intermediate 1 (200 mg, 0.39 mmol),trimethylsilylacetylene (112 μl, 0.78 mmol), tetrakis-triphenylphospinepalladium(0) (20 mg, 5 mol %), triphenyl phosphine (10 mg, 10 mol %) andcopper iodide (7.6 mg, 1 mol %) was made up in 2 ml of dry piperidineand added to a crimp top microwave vial. The vial was sealed, purgedwith nitrogen and then irradiated in the Smith Synthesizer Microwave to150° C. for 10 minutes. The reaction was diluted with EtOAc (100 ml) andthe mixture washed successively with dilute NaHCO₃, 1M HCl solution andthen saturated brine solution. The organic layer was then separated,dried (MgSO₄) and evaporated in vacuo giving a crude residue which waspurified by flash column chromatography using 25% EtOAc in isohexane aseluant to give the trimethylsilylethynyl derivative as a white solid(156 mg, 86% yield). δ (¹H, 400 MHz, CDCl₃) 0.23 (9H, s), 1.25–1.30 (2H,m), 1.68–1.72 (2H, m), 2.42–2.45 (2H, m), 2.62–2.71 (2H, m), 3.15–3.22(2H, m), 3.42 (2H, s), 3.67 (2H, q, J=8.7 Hz), 4.68 (1H, brs), 7.03 (1H,d, J=8.2 Hz) and 7.22–7.24 (2H, m).

Step 2

A solution of the product of Step 1 (156 mg, 0.34 mmol) in a 10:1tetrahydrofuran/water mixture (10 ml) was treated with lithium hydroxide(41 mg, 1.71 mmol) and stirred at room temperature for 1.5 hours. Thereaction mixture was diluted with 50 ml dichloromethane and washed withsaturated brine solution. The organic phase was dried (MgSO₄) andevaporated to dryness before purification by flash column chromatographyusing 20% ethyl acetate in isohexane as eluant to give the ethynylderivative as a colourless film (86 mg, 66%). δ (¹H, 400 MHz, CDCl₃)1.28–1.32 (2H, m), 1.68–1.72 (2H, m), 2.42–2.46 (2H, m), 2.62–2.71 (2H,m), 3.05 (1H, s), 3.15–3.22 (2H, m), 3.43 (2H, s), 3.67 (2H, q, J=8.7Hz), 4.66 (1H, brs), 7.03 (1H, d, J=8.2 Hz) and 7.22–7.24 (2H, m).

Step 3

A mixture of the acetylene derivative from Step 2 (32.5 mg, 0.085 mmol),2-bromopyridine (20 mg, 0.127 mmol), tetrakis-triphenylphospinepalladium(0) (8 mg, 10 mol %), triphenyl phosphine (2 mg, 10 mol %) andcopper iodide (1.7 mg, 10 mol %) in dry piperidine (2 ml) was added to acrimp top microwave vial, which was then sealed, purged with nitrogenand irradiated in the Smith Synthesizer Microwave to 140° C. for 10minutes. After this time the reaction was diluted with EtOAc (30 ml) andthe mixture washed successively with dilute NaHCO₃, 1M HCl solution andthen saturated brine solution. The organic layer was separated, dried(MgSO₄) and evaporated in vacuo, giving a crude residue which was takenup in 1 ml DMSO and purified by mass directed HPLC. δ (¹H, 400 MHz,CDCl₃) 1.26–1.35 (2H, m), 1.71–1.75 (2H, m), 2.47 (2H, m), 2.65–2.75(2H, m), 3.12–3.22 (2H, dd), 3.43 (2H,s), 3.65–3.71 (2H, q), 4.8 (1H,brs), 7.1 (1H, m), 7.37–7.40 (2H, m), 7.42–7.47 (1H, m), 7.59–7.62 (1H,m), 7.88–7.93 (1H, m), 8.72 (1H, m). (ES+) 462 ([MH]⁺).

Example 3

Prepared as in Example 2, using 3-bromopyridine in Step 3. δ (¹H, 400MHz, CDCl₃) 1.26–1.35 (2H, m), 1.71–1.75 (2H, m), 2.47 (2H, m),2.65–2.75 (2H, m), 3.12–3.22 (2H, dd), 3.43 (2H,s), 3.65–3.71 (2H, q),4.68 (1H, brs), 7.1 (1H, m), 7.31–7.33 (2H, m), 7.48–7.51 (1H, m),7.90–8.02 (1H, m), 8.60–8.62 (1H, m), 8.82 (1H, s). (ES+) 462 ([MH]⁺).

Example 4

Prepared as in Example 2, using iodopyrazine in Step 3. δ (¹H, 400 MHz,CDCl₃) 1.31–1.34 (2H, m), 1.72–1.76 (2H, m), 2.46–2.49 (2H, m),2.68–2.77 (2H, m), 3.21–3.27 (2H, dd), 3.44 (2H, s), 3.65–3.71 (2H, q),4.71 (1H, brs), 7.12–7.14 (1H, d), 7.38–7.39 (2H, m), 8.48 (1H, d), 8.57(1H, m), 8.74 (1H, s). (ES+) 463 ([MH]⁺).

Example 5

Step 1

1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (3.3 g, 17.4 mmol) wasadded to a mixture of 6-heptynoic acid (1.1 g, 8.7 mmol), benzylamine(950 μl, 8.7 mmol), 1-hydroxybenzotriazole (1.2 g, 8.7 mmol) andtriethylamine (2.4 ml, 17.4 mmol) in tetrahydrofuran (25 ml) and themixture was stirred at room temperature for 16 hours. The reaction wasdiluted with sodium hydrogen carbonate (sat, 60 ml) and extracted withethyl acetate (2×100 ml). The extracts were washed with brine, dried(MgSO₄) and evaporated in vacuo to provide 6-heptynoic acidN-benzylamide as a brown solid (2.1 g, 99%). (ES+) 216 ([MH]⁺).

Step 2

Lithium aluminium hydride (1 m in THF, 10 ml, 10 mmol) was added to asolution of the amide from Step 1 (1.0 g, 4.6 mmol) in THF (20 ml) andthe mixture was heated at reflux for 16 hours. The reaction was cooledin ice and treated successively with water (0.4 ml), sodium hydroxide(0.4 ml) and water (1.2 ml) allowing 10 minutes between additions. Themixture was filtered through a bed of Celite® and washed through withTHF. The filtrate was evaporated in vacuo to provide7-(N-benzylamino)hept-1-yne as a yellow oil (924 mg, 99%). (ES+) 202([MH]⁺).

Step 3

A mixture of Intermediate 1 (300 mg, 0.6 mmol), the alkyne from Step 2)(482 mg, 2.4 mmol), tetrakis-triphenylphospine palladium(0) (35 mg, 5mol %), triphenyl phosphine (16 mg, 10 mol %) and copper iodide (12 mg,10 mol %) in triethylamine (5 ml) in a sealed tube was purged withnitrogen and then heated at 90° C. for 16 hours. The reaction wasdiluted with sodium hydrogen carbonate (sat, 30 ml) and extracted withethyl acetate (2×20 ml). The extracts were washed with water (×3) andbrine, dried (MgSO₄) and evaporated in vacuo to a dark oil, which waspurified by flash column chromatography on silica eluting withDCM:MeOH:NH₃(aq) (120:8:1) to give a brown gum. The gum was furtherpurified flash column chromatography on silica eluting with EtOAc inisohexane (50%+1% NH₃(aq)) to give the title compound as a clear foam(241 mg, 72%). δ (¹H, 400 MHz, CDCl₃) 1.28–1.32 (2H, m), 1.45–1.71(8H,m), 2.38–2.44 (4H, m), 2.60–2.70 (4H, m), 3.16 (2H, dd, J=16.0 & 10.1Hz), 3.42 (2H, s), 3.67 (2H, q, J=8.6 Hz), 3.79 (2H, s), 7.00 (1H, d,J=7.8 Hz), 7.13–7.16 (2H, m), and 7.22–7.32 (4H, m). (ES+) 560 ([MH]⁺).

Example 6

Step 1

A mixture of Intermediate 1, (150 mg, 0.3 mmol), the amide from Example5, Step 1 (258 mg, 1.2 mmol), tetrakis-triphenylphospine palladium(0)(17 mg, 5 mol %), triphenyl phosphine (8.6 mg, 10 mol %) and copperiodide (6 mg, 10 mol %) in triethylamine (4 ml) in a sealed tube, waspurged with nitrogen and then heated at 100° C. for 16 hours. Dioxane (4ml) and tetrakis-triphenylphospine palladium(0) (17 mg, 5 mol %),triphenyl phosphine (8.6 mg, 10 mol %) and copper iodide (6 mg, 10 mol%) were added and the reaction was heated at 100° C. for 16 hours. Thereaction was diluted with sodium hydrogen carbonate (sat, 30 ml) andextracted with ethyl acetate (2×20 ml). The extracts were washed withwater (×3) and brine, dried (MgSO₄) and evaporated in vacuo to a browngum, which was purified by flash column chromatography on silica elutingwith EtOAc:isohexane (3:2) to give a beige foam (79 mg, 46%). δ (¹H, 400MHz, CDCl₃) 1.24–1.32 (2H, m), 1.63–1.72 (4H, m), 1.83–1.87 (2H, m),2.27 (2H, t, J=7.6 Hz), 2.43 (2H, t, J=), 2.60–2.70 (2H, m), 3.17 (2H,dd, J=16.0 & 11.4 Hz), 3.42 (2H, s), 3.67 (2H, q, J=8.7 Hz), 4.45 (2H,d, J=5.7 Hz), 4.70 (1H, Brs), 5.70 (1H, Brs), 6.99 (1H, d, J=8.2 Hz),7.13–7.14 (2H, m), and 7.27–7.33 (5H, m). (ES+) 574 ([MH]⁺).

Example 7

Step 1

A solution of 3-butyn-1-ol (5.0 ml, 77 mmol) in THF (20 ml) was added toa suspension of hexane-washed sodium hydride (3.7 g, 92.5 mmol) in THF(50 ml), under a nitrogen atmosphere at 0° C. The reaction was stirredat 0° C. for 90 minutes before a solution of chloroacetonitrile (5.9 ml,92.5 mmol) in THF (20 ml) was added dropwise. The black solution wasstirred at 0° C. for 15 minutes and at room temperature for 16 hours.The reaction was quenched by the careful addition of brine (150 ml) andthe mixture was concentrated in vacuo. The residue was extracted withDCM (3×100 ml). The extracts were dried (MgSO₄) and evaporated in vacuoto a dark oil, which was purified by flash column chromatography onsilica eluting with EtOAc:isohexane (1:9) to give3-butyn-1-yloxyacetonitrile as a yellow liquid (777 mg, 9%). (ES+) 110([MH]⁺).

Step 2

A mixture of Intermediate 1 (508 mg, 1.0 mmol), the alkyne from Step 1(218 mg, 2.0 mmol), tetrakis-triphenylphospine palladium(0) (58 mg, 5mol %), triphenyl phosphine (26 mg, 10 mol %) and copper iodide (20 mg,10 mol %) in triethylamine (2 ml) and dioxane (2 ml) in a sealed tube,was purged with nitrogen and then heated at 100° C. for 16 hours. Thereaction was diluted with sodium hydrogen carbonate (sat, 20 ml) andextracted with ethyl acetate (2×20 ml). The extracts were washed withwater (2×20 ml) and brine, dried (MgSO₄) and evaporated in vacuo to abrown gum, which was purified by flash column chromatography on silicaeluting with EtOAc:isohexane (20 to 25 to 30%) to give a pale foam (354mg, 76%). δ (¹H, 400 MHz, CDCl₃) 1.24–1.32 (2H, m), 1.68–1.72 (2H, m),2.43 (2H, t, J=7.0 Hz), 2.60–2.76 (4H, m), 3.18 (2H, dd, J=16.0 & 8.2Hz), 3.64–3.70 (2H, m), 3.79 (2H, t, J=6.7 Hz), 4.33 (2H, s), 4.68 (1H,Brs), 7.00 (1H, d, J=8.2 Hz), and 7.16–7.18 (2H, m). (ES+) 468 ([MH]⁺).

Example 8

Lithium aluminium hydride (1M in THF, 0.71 ml, 0.71 mmol) was added to acold (0° C.) solution of the nitrile from Example 7 Step 2 (330 mg, 0.71mmol) in THF (10 ml) and the mixture was stirred at 0° C. for 2 hours.The reaction was treated successively with water (28 μl), sodiumhydroxide (28 μl) and water (84 μl) allowing 10 minutes betweenadditions. The mixture was filtered through a bed of Celite® and washedthrough with THF. The filtrate was evaporated in vacuo to a gummy solidwhich was purified by SCX ion exchange resin eluting with ammonia (2M inmethanol) to give after evaporation a pale yellow gum (195 mg, 58%). δ(¹H, 400 MHz, CDCl₃) 1.25–1.34 (2H, m), 1.67–1.71 (2H, m), 2.41–2.44(2H, m), 2.60–2.71 (4H, m), 2.84–2.90 (2H, m), 3.17 (2H, dd, J=16.0 &8.2 Hz), 3.42 (2H, s), 3.48–3.50 (2H, m), 3.49–3.70 (4H, m), 7.00 (1H,d, J=8.2 Hz), and 7.15–7.17 (2H, m).

(ES+) 472 ([MH]⁺).

Example 9

A mixture of Intermediate 1 (100 mg, 0.2 mmol), 6-heptynoic (101 μl, 0.8mmol), tetrakis-triphenylphospine palladium(0) (12 mg, 5 mol %),triphenyl phosphine (5.2 mg, 10 mol %) and copper iodide (4 mg, 10 mol%) in triethylamine (2 ml) and dioxane (2 ml) was purged with nitrogenand then heated at 100° C. for 16 hours. The reaction was diluted withhydrochloric acid (1N) and extracted with ethyl acetate (2×25 ml). Theextracts were washed with water (×3) and brine, dried (MgSO₄) andevaporated in vacuo to a yellow gum, which was purified by flash columnchromatography on silica eluting with EtOAc:isohexane (1:3) to give afoam which was further purified by preparative TLC eluting withEtOAc:isohexane (1:3) to give a clear gum (11 mg, 12%). δ (¹H, 400 MHz,CDCl₃) 1.25–1.34 (2H, m), 1.57–1.84 (6H, m), 2.32–2.46 (8H, m),2.55–2.69 (2H, m), 3.18 (2H, dd, J=16.0 & 9.7 Hz), 3.42 (2H, s), 3.67(2H, q, J=8.7 Hz), 7.00 (1H, d, J=8.2 Hz), and 7.14–7.16 (2H, m).

(ES+) 483 ([MH]⁻).

1. A compound of formula I:

wherein X represents Ar, L-N(R¹)₂, L-CON(R¹)₂, L-CO₂R¹ or L-CN; Lrepresents a hydrocarbon chain of 1–7 carbon atoms which, when the chainconsists of 2 or more carbon atoms, is optionally interrupted by anoxygen atom; R¹ represents H or R²; or two R¹ groups attached to asingle nitrogen atom may complete a heterocyclic ring of 3–7 membersbearing 0–3 substituents selected from halogen, oxo, NO₂, CN, CF₃, R²,C₂₋₆acyl, C₂₋₆alkenyl, OH, OR², CO₂H, CO₂R², Ar, ArCH₂O, and ArO; R²represents C₁₋₆alkyl which is optionally substituted with halogen, Ar,NO₂, CN, CF₃, OH or C₁₋₄alkoxy; R¹⁴ represents H or C₁₋₆alkyl,C₃₋₇cycloalkyl, C₃₋₆cycloalkylC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,phenyl or benzyl, any of which optionally bear up to 3 halogensubstituents or one substituent selected from CN, NO₂, OH, C₁₋₄alkoxy,CO₂H, C₁₋₄alkoxycarbonyl, C₂₋₆acyl, C₂₋₆acyloxy, amino, C₁₋₄alkylamino,di(C₁₋₄alkyl)amino, C₂₋₆acylamino, carbamoyl, C₁₋₄alkylcarbamoyl anddi(C₁₋₄alkyl)carbamoyl; and Ar represents phenyl or heteroaryl either ofwhich optionally bears up to 3 substituents independently selected fromhalogen, CF₃, NO₂, CN, OCF₃, C₁₋₆alkyl and C₁₋₆alkoxy; or apharmaceutically acceptable salt thereof.
 2. A compound according toclaim 1 wherein X represents Ar and Ar represents optionally-substitutedphenyl, pyridyl, pyrimidinyl or pyrazinyl.
 3. A compound according toclaim 1 wherein L is selected from —CH₂—, —(CH₂)₄—, —(CH₂)₅—,—(CH₂)₂—O—(CH₂)₂— and —(CH₂)₂—O—CH₂—.
 4. A compound according to claim 1of formula II:

or a pharmaceutically acceptable salt thereof.
 5. A compound accordingto claim 4 wherein X is selected from 6-membered heteroaryl, —CH₂N(R¹)₂,—(CH₂)₅N(R¹)₂—(CH₂)₄CON(R¹)₂, —(CH₂)CO₂R², —(CH₂)₂—O—CH₂CN and—(CH₂)₂—O—(CH₂)₂N(R¹)₂.
 6. A compound according to claim 5 wherein X isselected from 2-pyridyl, 3-pyridyl, pyrazinyl,4-trifluoropiperidin-1-ylmethyl, —(CH₂)₅NH—CH₂Ph, —(CH₂)₄CONHCH₂Ph,—(CH₂)₄CO₂H, —(CH₂)₂—O—CH₂CN and —(CH₂)₂—O—(CH₂)₂NH₂.
 7. Apharmaceutical composition comprising a compound according to anyprevious claim and a pharmaceutically acceptable carrier.
 8. A method oftreatment of a subject suffering from Alzheimer's disease whichcomprises administering to that person an effective amount of a compoundaccording to any of claims 1–6.